The present invention is concerned with the use of 17xcex2-N-monosubstituted-carbamoyl-4-aza-5xcex1-androst-1-en-3-one compounds as testosterone-5xcex1-reductase inhibitors for the prevention of prostatic carcinoma.
There is no drug which is known to prevent prostatic cancer to date. Most forms of androgen withdrawal result in sexual dysfunction and gynecomotia making them unacceptable for prevention therapy.
It is further well known in the art that certain undesirable physiological manifestations, such as acne vulgaris, seborrhea, female hirsutism, male pattern baldness and benign prostatic hypertrophy, are the result of hyperandrogenic stimulation caused by an excessive accumulation of testosterone or similar androgenic hormones in the metabolic system. It is also established that androgens play an important role in prostatic carcinoma. Boys castrated prior to puberty or with a metabolic deficiency of androgens do not develop prostatic cancer. Early attempts to provide a chemotherapeutic agent to counter the undesirable results of hyperandrogenicity resulted in the discovery of several steroidal antiandrogens having undesirable hormonal activities of their own. The estrogens, for example, not only counteract the effect of the androgens but have a feminizing effect as well. Non-steroidal anti-androgens have also been developed, for example, 4xe2x80x2-nitro-3xe2x80x2-trifluoromethyl-isobutyranilide. See Neri et al., Endo., Vol. 91, No. 2 (1972). However, these products, though devoid of hormonal effects, are peripherally active, competing with the natural androgens for receptor sites, and hence have a tendency to feminize a male host or the male fetus of a female host.
It more recently became known in the art that the principal mediator of androgenic activity in some target organs is 5xcex1-dihydrotestosterone, and that it is formed locally in the target organ by the action of testosterone-5xcex1-reductase. It therefore has been postulated and demonstrated that inhibitors of testosterone-5xcex1-reductase will serve to prevent or lessen symptoms of hyperandrogenic stimulation. Nayfe et al., Steroids, 14, 269 (1969) demonstrated in vitro that methyl 4-androsten-3-one-17xcex2-carboxylate was a testosterone-5xcex1-reductase inhibitor. Then Voigt and Hsia, Endocrinology, 92, 1216 (1973), Canadian Pat. No. 970,692, demonstrated that the above ester and the parent free acid, 4-androsten-3-one-17xcex2-carboxylic acid are both active inhibitors of testosterone-5xcex1-reductase in vitro. They further demonstrated that topical application of either testosterone or 5xcex1-dihydrotesterone caused enlargement of the female hamster flank organ, an androgen dependent sebaceous structure. However, concommitant administration of 4-androsten-3-one-17xcex2-carboxylic acid or its methyl ester inhibited the response elicited by testosterone but did not inhibit the response elicited by 5xcex1-dihydrotestosterone. These results were interpreted as indicating that the compounds were antiandrogenic by virtue of their ability to inhibit testosterone-5xcex1-reductase.
A number of 4-aza steroid compounds are known. See, for example, U.S. Pat. Nos. 2,227,876; 3,239,417; 3,264,301; and 3,285,918; French Pat. No. 1,465,544; Doorenbos and Solomons, J. Pharm. Sci. 62, 4, pp. 638-640 (1973); Doorenbos and Brown, J. Pharm. Sci., 60, No. 8, pp. 1234-1235 (1971); and Doorenbos and Kim, J. Pharm. Sci. 63, 4, pp. 620-622 (1974).
In addition, U.S. Pat. Nos. 4,377,584, 4,220,775, 4,760,071, 4,859,681 and 5,049,562 of Rasmusson et al. describe a group of 4-aza-17xcex2-substituted-5xcex1-androstan-3-ones which are said to be useful in the treatment of hyperandrogenic conditions. However, none of the cited references suggest that any of the novel 17xcex2N-(monosubstituted) carbamoyl-4-aza-5xcex1-androst-1-en-3-ones of the present invention would have utility in preventing prostatic cancer.
The present invention is concerned with preventing prostatic cancer in humans, who are asymptomatic for the disease by treating the patients with 17xcex2-N-(monosubstituted)-carbamoyl-4-aza-5xcex1-androst-1-en-3-one compounds. By the term xe2x80x9casymptomaticxe2x80x9d as used herein, is meant that overt signs of the disease are not present, or indicated, e.g., lumps or cysts on the prostate wall. However, the patient may or may not have elevated levels of prostate specific antigen (PSA) at the start of therapy, due to the concomitant condition of benign prostatic hyerplasia.
There is no other known way to achieve this with acceptable side effects. The compounds described herein, and specifically finasteride, i.e., 17xcex2-(N-tert-butylcarbamoyl)-4-aza-5xcex1-androst-1-en-3-one, will lower DHT to castrate levels without lowering testosterone levels and will, therefore, not produce undesirable sexually related side effects. A daily dosage of 1-10 mg p.o. (oral) per person of finasteride will prevent men from developing prostatic cancer.
The present invention is concerned with compounds of the formula: 
wherein
R1 is hydrogen, methyl or ethyl.
R2 is a hydrocarbon radical selected from straight or branched chain alkyl, cycloalkyl, or aralkyl of from 1-12 carbons or monocyclic aryl optionally containing 1 or more lower alkyl substituents of from 1-2 carbon atoms and/or 1 or more halogen (Cl, F or Br) substituents.
Rxe2x80x2 is hydrogen or methyl.
Rxe2x80x3 is hydrogen or B-methyl.
Rxe2x80x2xe2x80x3 is hydrogen, xcex1a-methyl or xcex2-methyl.
A preferred embodiment of the compounds applicable in the process of our invention is represented by the formula: 
wherein
R1 is hydrogen, methyl or ethyl, and
R3 is branched chain alkyl, cycloalkyl, or aralkyl of from 4-10 carbons.
Representative compounds of the present invention include the following:
17xcex2-(N-tert-amylcarbamoyl-4-aza-5xcex1-androst-1-en-3-one,
17xcex2-(N-tert-hexylcarbamoyl)-4-aza-5xcex1-androst-1-en-3-one,
17xcex2-(N-tert-butylcarbamoyl)-4-aza-5xcex1-androst-1-en-3-one,
17xcex2-(N-isobutylcarbamoyl)-4-aza-5xcex1-androst-1-en-3-one,
17xcex2-(N-tert-octylcarbamoyl)-4-aza-5xcex1-androst-1-en-3-one,
17xcex2-(N-octylcarbamoyl)-4-aza-5xcex1-androst-1-en-3-one,
17xcex2-(N-1,1-diethylbutylcarbamoyl)-4-aza-5xcex1-androst-1-en-3-one,
17xcex2-(N-neopentylcarbamoyl)-4-aza-5xcex1-androst-1-en-3-one,
17xcex2-(N-2-adamantylcarbamoyl)-4-aza-5xcex1-androst-1-en-3-one,
17xcex2-(N-1-adamantylcarbamoyl)-4-aza-5xcex1-androst-1-en-3-one,
17xcex2-(N-2-norbornylcarbamoyl)-4-aza-5xcex1-androst-1-en-3-one,
17xcex2-(N-1-norbornylcarbamoyl)-4-aza-5xcex1-androst-1-en-3-one,
17xcex2-(N-phenylcarbamoyl)-4-aza-4-methyl-5xcex1-androst-1-en-3-one,
17xcex2-(N-benzylcarbamoyl)-4-aza-4-methyl-5xcex1-androst-1-en-3-one,
17xcex2-(N-tert-amylcarbamoyl-4-aza-4-methyl-5xcex1-androst-1-en-3-one,
17xcex2-(N-tert-hexylcarbamoyl)-4-aza-4-methyl-5xcex1-androst-1-en-3-one,
17xcex2-(N-tert-butylcarbamoyl)-4-aza-4-methyl-5xcex1-androst-1-en-3-one,
17xcex2-(N-isobutylcarbamoyl)-4-aza-4-methyl-5xcex1-androst-1-en-3-one,
17xcex2-(N-tert-octylcarbamoyl)-4-aza-4-methyl-5xcex1-androst-1-en-3-one,
17xcex2-(N-octylcarbamoyl)-4-aza-4-methyl-5xcex1-androst-1-en-3-one,
17xcex2-(N-1,1-diethylbutylcarbamoyl)-4-aza-4-methyl-5xcex1-androst-1-en-3-one,
17xcex2-(N-neopentylcarbamoyl)-4-aza-4-methyl-5xcex1-androst-1-en-3-one, and the corresponding compounds wherein the 4-hydrogen substituent is replaced in each of the above named compounds by a hydrogen or an ethyl radical and vice versa.
Also included as representative compounds are any of the above indicated compounds having the N-branched chain alkyl substituent replaced by a methyl, ethyl, propyl, i-propyl, butyl, phenyl, benzyl, 2-, 3- or 4-tolyl, xylyl, 2-bromo or 2-chlorophenyl, 2-6-dichloro, or a 2,6-dibromophenyl substituent.
The compounds of formula I of the present invention are prepared by a method starting with the known steroid ester of the formula: 
17xcex2-(carbomethoxy)-4-aza-5xcex1-androstan-3-one which includes the stages of: (1) dehydrogenating said starting material to produce the corresponding compound containing a double-bond in the 1,2-position of the A-ring; (2) converting the 17-carbomethoxy substituent into an N-monosubstituted carbamoyl substituent and, if desired; and (3) alkylating the A-ring nitrogen to introduce a N-methyl or 4-ethyl substituent into the A ring. In carrying out the process of the present invention, it is essential that Stage 1 dehydrogenation of the 1,2-position of the steroid A ring be carried out using a 4-aza-5xcex1-androstane-3-one-compound having no substituent other than hydrogen attached to the A-ring nitrogen. Stage 2 may consist of one or more chemical steps, and if desired may take place before stage (1) or following stage (1) or stage (3).
In accordance with the process of the present invention, the products of our invention are formed by (1) heating a 17xcex2-alkoxycarbonyl-4-aza-5xcex1-androstan-3-one compound III with a dehydrogenating agent such as benzeneselenic anhydride in refluxing chlorobenzene to form a 17xcex2-alkoxycarbonyl-4-aza-5xcex1-androst-1-ene-3-one IV; (2) the formed 5xcex1-androst-1-en-3-one compound from Step 1 is reacted with sodium hydride under anhydrous conditions in a neutral solvent such as dimethylformamide; (3) contacting the resulting reaction mixture with an alkyl (methyl or ethyl) iodide to form the corresponding 17-xcex2-alkoxy-carbamoyl-4-alkyl-4-aza-5xcex1-androst-1-en-3-one V; (4) subsequently hydrolyzing said 17xcex2-alkoxycarbonyl-4-alkyl-4-aza-5xcex1-androst-1-en-3-one with a strong base such as aqueous methanolic potassium hydroxide at the reflux temperature, followed by acidification and isolation of the resulting steroidal acid, 17xcex2-carboxy 4-alkyl-4-aza-5xcex1-androst-1-en-3-one VI: (5) said steroidal acid is then converted to its corresponding 2-pyridylthio ester by refluxing with triphenyl phosphine and 2,2xe2x80x2-dipyridyl disulfide in an inert solvent such as toluene and the resulting product 17xcex2-(2-pyridylthiocarbonyl)-4-alkyl-4-aza-5xcex1-androst-1-en-3-one VII is isolated by chromatography on silica gel: (6) said pyridylthio ester is then reacted with an appropriate primary amine, e.g. t-butylamine, n-butylamine, aniline, bencylamine, t-octylamine, amine in tetrahydrofuran to form the desired products 17xcex2-N-substituted carbamoyl-4-alkyl-4-aza-5xcex1-androst-1-en-3-one VIII which is isolated by chromatography on silica gel.
In accordance with the process of our invention the corresponding 17xcex2(N-R2-carbamoyl)-4-aza-5xcex1-androst-1-en-3-one XIV is readily prepared from the 17xcex2(alkoxycarbonyl)-4-aza-5xcex1-androstone-3-one IV by repeating the above series of reaction steps but omitting Step 2 herein above, i.e. treatment of the 4-aza-5-xcex1-androst-1-en-3-one with sodium amide followed by methyl or ethyl iodide via intermediates XII and XIII.
In accordance with a further alternate process of preparing the compounds of our invention having only hydrogen as the sole substituent on the ring Axe2x80x94nitrogen, the double bond in the A ring is introduced as the last step of the process. Thus, a 17xcex2-alkoxycarbonyl 4-aza-5xcex1-androstan-3-one III is hydrolyzed to the corresponding steroidal acid IX 17xcex2-carboxy-4-aza-5xcex1-androstan-3-one which in turn is converted to the corresponding pyridylthio ester, 17xcex2(2-pyridylthiocarbonyl)-4-aza-5xcex1-androstan-3-one, X followed by treatment of the ester with an amine of formula R2xe2x80x94NH2 wherein R2 is as defined hereinabove to form a 17xcex2(N-R2-carbamoyl)-4-aza-5xcex1-androstone-3-one XI which is dehydrogenated as previously described to produce compound XIV, 17xcex2-(N-R2-carbamoyl)-4-aza-androst-1-en-3-one.
In another alternate method of introducing the 17xcex2-(N-R2-carbamoyl)substituent into a 17xcex2-carboxy, androstane compound of formula VI, XII or IX, each is treated in a manner similar to the procedure described in Steroids, Vol. 35 #3, March 1980, p. 1-7 with dicyclohexylcarbodiimide and 1-hydroxybenzotriazole to form the 17xcex2-(1-benzotriazoloxycarbonyl)-4-aza-5xcex1-androst-1-en-3-one, VII, XIII or X, wherein X is 1-benzotriazoloxy or 17xcex2-(1-benzotriazoloxycarbonyl)-4-aza-5xcex1-androstan-3-one, X.
The above reactions are schematically represented in the following structural formula outline. 
X is 2-pyridylthio or benzotriazoloxy
The compounds of the present invention, prepared in accordance with the method described above, are, as already described, potent and selective antiandrogens in the prevention of prostatic cancer, by virtue of their ability to specifically inhibit testosterone-5xcex1-reductase.
Accordingly, the present invention is particularly concerned with providing a method of treating prostatic carcinoma in human males by systemic or oral administration of the novel compounds of the present invention.
The present invention is thus also concerned with providing suitable topical and systemic pharmaceutical formulations for use in the novel methods of treatment of the present invention.
The compositions containing the compounds of the present invention as the active ingredient for use in the prevention of prostatic carcinoma can be administered in a wide variety of therapeutic dosage forms in conventional vehicles for systemic administration, as, for example, by oral administration in the form of tablets, capsules, solutions, or suspensions, of by intravenous injection. The daily dosage of the products may be varied over a wide range varying from 1 to 2,000 mg per person, preferably from 1 to 200 mg. and particularly preferred from 1 to 20 mg per person. The compositions are preferably provided in the form of scored tablets containing 0.1, 1, 5, 10, 25, 50, 100, 150, 250, and 500 milligrams of the active ingredient for the symptomatic adjustment of the dosage to the patient to be treated. An effective amount of the drug is ordinarily supplied at a dosage level of from about 0.01 mg. to about 50 mg./kg. of body weight per day. Preferably the range is from about 0.1 mg. to 7 mg./kgs. of body weight per day and more preferably from about 0.1 mg to about 3 mg/kg of body weight per day. These dosages are well below the toxic dose of the product. Capsules containing the product of this invention can be prepared by mixing an active compound of the present invention with lactose and magnesium stearate, calcium stearate, starch, talc, or other carriers, and placing the mixture in gelatin capsule. Tablets may be prepared by mixing the active ingredient with conventional tableting ingredients such as calciuim phosphate, lactose, corn starch or magnesium stearate. The liquid forms in suitably flavored suspending or dispersing agents such as the synthetic and natural gums, for example, tragacanth, acacia, methylcellulose and the like. Other dispersing agents which may be employed include glycerin and the like. For parenteral administration, sterile suspensions and solutions are desired. Isotonic preparations which generally contain suitable preservative are employed when intravenous administration is desired.